DNA damaging and cell proliferative activity of 1-methyl-1-nitrosourea in rat glandular stomach mucosa

Abstract

The DNA damaging and cell proliferative activity of 1-methyl-1-nitrosourea (MNU), a glandular stomach carcinogen, was studied in the pyloric mucosa of male F344 rats after administration by gastric tube. DNA damage was measured with unscheduled DNA synthesis (UDS) and DNA single strand scission as markers, while cell proliferation was measured with replicative DNA synthesis (RDS) and ornithine decarboxylase (ODC) as markers. MNU at doses of 30 and 60 mg/kg body wt and 80 min after administration dose-dependently induced UDS (49 and 79 (0 dose, 19) dpm/μg DNA) measured by liquid scintillation counting in the presence of hydroxyurea (an inhibitor of RDS). RDS (DNA synthesis in the absence of hydroxyurea; 239 dpm/μg DNA at 0 dose) did not increase at that time. MNU at doses of 10 and 60 mg/kg body wt and 2 h after administration dose-dependently induced DNA single strand scission of 8.2 and 43.5 (0 dose, 1.4) elution rate constant (×10⁻³/ml). MNU at doses of 30 and 60 mg/kg body wt and 24 h after administration dose-dependently induced an increase in RDS (1362 and 2393 (0 dose, 682) dpm/μg DNA). MNU at doses of 60, 90 and 120 mg/kg body wt and 24 h after administration dose-dependently induced an increase in ODC activity (22.0, 29.4 and 38.4 (0 dose, 6.3) p mol CO₂/30 min/mg protein). These results suggest that MNU has possible tumor initiating activity (UDS and DNA single strand scission) and tumor promoting activity (RDS and ODC) in rat stomach mucosa.